This invention relates generally to aryl sulfonyls, which are inhibitors of trypsin-like serine protease enzymes, especially factor Xa, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders.
WO 95/14683 and WO 96/38426 describe isoxazoline and isoxazole fibrinogen receptor antagonists of the formula: 
wherein R1 may be a basic group, Uxe2x80x94V may be a six-membered aromatic ring, Wxe2x80x94X may be a variety of linear or cyclic groups, and Y is an oxy group. Thus, these compounds all contain an acid functionality (i.e., Wxe2x80x94Xxe2x80x94C(xe2x95x90O)xe2x80x94Y). In contrast, the presently claimed compounds do not contain such an acid functionality.
WO 94/24095 describes isoxazole immunosuppressive agents of the formula: 
wherein D may be a variety of groups including H, phenyl, alkyl, and acyl, and E and G may be a variety of groups including aryl and heterocycle. However, the presently claimed aryl sulfonyls are not exemplified or discussed.
EP 0,513,387 depicts active oxygen inhibitors which are oxazoles or thiazoles of the formula: 
wherein X is O or S, R2 is preferably hydrogen, and both R1 and R3 are substituted cyclic groups, with at least one being phenyl. The presently claimed invention does not relate to these types of oxazoles or thiazoles.
WO 95/18111 addresses fibrinogen receptor antagonists, containing basic and acidic termini, of the formula: 
wherein R1 represents the basic termini, U is an alkylene or heteroatom linker, V may be a heterocycle, and the right hand portion of the molecule represents the acidic termini. The presently claimed compounds do not contain the acidic termini of WO 95/18111.
In U.S. Pat. No. 5,463,071, Himmelsbach et al depict cell aggregation inhibitors which are 5-membered heterocycles of the formula: 
wherein the heterocycle may be aromatic and groups Axe2x80x94Bxe2x80x94Cxe2x80x94 and Fxe2x80x94Exe2x80x94Dxe2x80x94 are attached to the ring system. Axe2x80x94Bxe2x80x94Cxe2x80x94 can be a wide variety of substituents including a basic group attached to an aromatic ring. The Fxe2x80x94Exe2x80x94Dxe2x80x94 group, however, would appear to be an acidic functionality which differs from the present invention. Furthermore, use of these compounds as inhibitors of factor Xa is not discussed.
Illig et al, in WO 97/47299, illustrate amidino and guanidino heterocycle protease inhibitors of the formula:
R1xe2x80x94Zxe2x80x94Xxe2x80x94Yxe2x80x94W
wherein R1 can be a substituted aryl group, Z is a two carbon linker containing at least one heteroatome, X is a heterocycle, Y is an optional linker and W is an amidino or guanidino containing group. Compounds of this sort are not considered part of the present invention.
Jackson et al, in WO 97/32583, describe cytokine inhibitors useful for inhibiting angiogenesis. These inhibitors include imidazoles of the formula: 
wherein R1 is a variety of heteroaryl groups, R4 is phenyl, naphthyl, or a heteroaryl group, and R2 can be a wide variety of groups. Jackson et al do not teach inhibition of factor Xa. Furthermore, the imidazoles of Jackson et al are not considered part of the present invention.
In U.S. Pat. No. 5,082,949, Sohn et al depict phenyl-pyrazole-carboxylic acids of the formula: 
wherein Y is a halogen, X is an acid or acid derivative, and R is selected from a variety of substituents. These compounds are indicated to have plant-growth regulating properties and also to be herbicide safeners. However, aryl sulfonyls, like those presently claimed, have not been described by Sohn et al, nor has the inhibition of factor Xa been described.
In U.S. Pat. No. 5,658,909, DeBernardis et al depict 1-aryl-3-piperazin-1xe2x80x2-yl propanones of the formula: 
wherein Ar1 can be a 5-membered heteroaryl substituted with an optionally substituted phenyl group, Y and R24 can each be H, Z can be N or CH and Ar2 can be phenyl or one of three heteroaryls. However, no aryl sulfonyls, like those presently claimed, have been described, nor has the inhibition of factor Xa been described.
Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca2+ and phospholipid). Since it is calculated that one molecule of factor Xa can generate 138 molecules of thrombin (Elodi, S., Varadi, K.: Optimization of conditions for the catalytic effect of the factor IXa-factor VIII Complex: Probable role of the complex in the amplification of blood coagulation. Thromb. Res. 1979, 15, 617-629), inhibition of factor Xa may be more efficient than inactivation of thrombin in interrupting the blood coagulation system.
Therefore, efficacious and specific inhibitors of factor Xa are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa inhibitors.
Accordingly, one object of the present invention is to provide novel nitrogen containing aromatic heterocycles, with ortho-substituted P1 groups, which are useful as factor Xa inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide novel compounds of formula (I) for use in therapy.
It is another object of the present invention to provide the use of novel compounds of formula (I) for the manufacture of a medicament for the treatment of a thromboembolic disorder.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula (I): 
or pharmaceutically acceptable salt or prodrug forms thereof, wherein D, E, and M are defined below, are effective factor Xa inhibitors.
[1] Thus, in an embodiment, the present invention provides a novel compound of formula I: 
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;
ring D is absent or selected from xe2x80x94CH2Nxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90NCH2xe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94CHxe2x95x90CHCH2xe2x80x94, xe2x80x94CH2CHxe2x95x90CHxe2x80x94, a 5-6 membered aromatic system containing from 0-2 heteroatoms selected from the group N, O, and S;
ring D, when present, is substituted with 0-2 R, provided that when ring D is unsubstituted, it contains at least one heteroatom;
E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, substituted with 0-1 R;
R is selected from Cl, F, Br, I, OH, C1-3 alkoxy, NH2, NH(C1-3 alkyl), N(C1-3 alkyl)2, CH2NH2, CH2NH(C1-3 alkyl), CH2N(C1-3 alkyl)2, CH2CH2NH2, CH2CH2NH(C1-3 alkyl), and CH2CH2N (C1-3 alkyl)2;
when ring D is absent, ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and ring E is substituted with G and Rxe2x80x2;
G is selected from F, Cl, Br, I, OH, C1-3 alkoxy, CN, C(xe2x95x90NR8)NR7R9, NHC(xe2x95x90NR8)NR7R9, NR8CH(xe2x95x90NR7), C(O)NR7R8, (CR8R9)tNR7R8, SH, C1-3 alkyl-S, S(O)R3b, S(O)2R3a, S(O)2NR2R2a, and OCF3;
Rxe2x80x2 is selected from H, F, Cl, Br, I, SR3, CO2R3, NO2, (CH2)tOR3, C1-4 alkyl, OCF3, CF3, C(O)NR7R8, and (CR8R9)tNR7R8;
alternatively, G and Rxe2x80x2 combine to form methylenedioxy or ethylenedioxy;
M is attached to ring E or ring D, when present, and is selected from the group: 
J is O or S;
Ja is NH or NR1a;
Z is selected from a bond, C1-4 alkylene, (CH2)rO(CH2)r, (CH2)rNR3(CH2)r, (CH2)rC(O)(CH2)r, (CH2)rC(O)O(CH2)r, (CH2)rOC(O)(CH2)r, (CH2)rC(O)NR3(CH2)r, (CH2)rNR3C(O)(CH2)r, (CH2)rOC(O)O(CH2)r, (CH2)rOC(O)NR3(CH2)r, (CH2)rNR3C(O)O(CH2)r, (CH2)rNR3C(O)NR3(CH2)r, (CH2)rS(O)p(CH2)r, (CH2)rSO2NR3(CH2)r, (CH2)rNR3SO2(CH2)r, and (CH2)rNR3SO2NR3(CH2)r, provided that Z does not form a Nxe2x80x94N, Nxe2x80x94O, Nxe2x80x94S, NCH2N, NCH2O, or NCH2S bond with ring M or group A;
R1a and R1b are independently absent or selected from xe2x80x94(CH2)rxe2x80x94R1xe2x80x2, xe2x80x94CHxe2x95x90CHxe2x80x94R1xe2x80x2, NCH2R1xe2x80x3, OCH2R1xe2x80x3, SCH2R1xe2x80x3, NH(CH2)2(CH2)tR1xe2x80x2, O(CH2)2(CH2)tR1xe2x80x2, and S(CH2)2(CH2)tR1xe2x80x2;
alternatively, R1a and R1b, when attached to adjacent carbon atoms, together with the atoms to which they are attached form a 5-8 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4 and which contains from 0-2 heteroatoms selected from the group consisting of N, O, and S;
alternatively, when Z is C(O)NH and R1a is attached to a ring carbon adjacent to Z, then R1a is a C(O) bound to Z by replacing the amide hydrogen of Z to form a cyclic imide;
R1xe2x80x2 is selected from H, C1-3 alkyl, F, Cl, Br, I, xe2x80x94CN, xe2x80x94CHO, (CF2)rCF3, (CH2)rOR2, NR2R2a, C(O)R2c, OC(O)R2, (CF2)rCO2R2c, S(O)pR2b, NR2(CH2)rOR2, CH(xe2x95x90NR2c)NR2R2a, NR2C(O)R2b, NR2C(O)NHR2b, NR2C(O)2R2a, OC(O)NR2aR2b, C(O)NR2R2a, C(O)NR2(CH2)rOR2, SO2NR2R2a, NR2SO2R2b, C3-6 carbocyclic residue substituted with 0-2 R4a, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;
R1xe2x80x3 is selected from H, CH(CH2OR2)2, C(O)R2c, C(O)NR2R2a, S(O)R2b, S(O)2R2b, and SO2NR2R2a;
R2, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2a, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, phenethyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2b, at each occurrence, is selected from CF3, C1-4 alkoxy, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2c, at each occurrence, is selected from CF3, OH, C1-4 alkoxy, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4b and containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
R3a, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
R3b, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
R3c, at each occurrence, is selected from C1-4 alkyl, and phenyl;
R3d, at each occurrence, is selected from H, OH, and C1-3 alkyl;
R3e, at each occurrence, is selected from H and CH3;
A is selected from:
C3-10 carbocyclic residue substituted with 0-2 R4, and
5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4; 
Xxe2x80x94Y combine to form a group selected from:
C(R3dR3e)C(R3dR3e), C(R3dR3e)C(R3dR3e)C(R3dR3e), NR4cC(R3dR3e), NR4cC(xe2x95x90O), NR4cC(xe2x95x90NH), NR4cC(R3dR3e)C(R3dR3e), NR4cC(R3dR3e)NR4c, NR4cC(xe2x95x90O)NR4c, NR4cC(xe2x95x90O)C(R3dR3e), C(R3dR3e)NR4c, C(R3dR3e)NR4cC(R3dR3e), C(R3dR3e)C(R3dR3e)NR4c, NR4cNR4c, NR4cNR4cC(R3dR3e), and C(R3dR3e)NR4cNR4c;
R4, at each occurrence, is selected from H, xe2x95x90O, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, NR2C(O)NR2R2a, CH(xe2x95x90NR2)NR2R2a, CH(xe2x95x90NS(O)2R5)NR2R2a, NHC(xe2x95x90NR2)NR2R2a, C(O)NHC(xe2x95x90NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2xe2x80x94C1-4 alkyl, NR2SO2R5, S(O)pR5, (CF2)rCF3, NCH2R1xe2x80x3, OCH2R1xe2x80x3, SCH2R1xe2x80x3, N(CH2)2(CH2)tR1xe2x80x2, O(CH2)2(CH2)tR1xe2x80x2, and S(CH2)2(CH2)tR1xe2x80x2;
alternatively, one R4 is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R4a is selected from H, xe2x95x90O, (CH2)rOR2, (CH2)rxe2x80x94F, (CH2)rxe2x80x94Br, (CH2)rxe2x80x94Cl, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR2R2a, (CH2)rNR2R2b, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, C(O)NH(CH2)2NR2R2a, NR2C(O)NR2R2a, CH(xe2x95x90NR2)NR2R2a, NHC(xe2x95x90NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2xe2x80x94C1-4 alkyl, C(O)NHSO2xe2x80x94C1-4 alkyl, NR2SO2R5, S(O)pR5, and (CF2)rCF3;
R4b, at each occurrence, is selected from H, xe2x95x90O, (CH2)rOR3, F, Cl, Br, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR3R3a, (CH2)rC(O)R3, (CH2)rC(O)OR3c, NR3C(O)R3a, C(O)NR3R3a, NR3C(O)NR3R3a, CH(xe2x95x90NR3)NR3R3a, NH3C(xe2x95x90NR3)NR3R3a, SO2NR3R3a, NR3SO2NR3R3a, NR3SO2xe2x80x94C1-4 alkyl, NR3SO2CF3, NR3 SO2-phenyl, S(O)pCF3, S(O)pxe2x80x94C1-4 alkyl, S(O)p-phenyl, and (CF2)rCF3;
R4c, at each occurrence, is selected from H, C1-4 alkyl, CH2xe2x80x94CN, (CH2)2xe2x80x94CN, CH2xe2x80x94NR2R2a, (CH2)2NR2R2a, CH2C(O)R2c, (CH2)2C(O)R2c, CH2xe2x80x94C(O)NR2R2a, (CH2)2C(O)NR2R2a, phenyl, and benzyl;
R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6;
R6, at each occurrence, is selected from H, OH, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2b, NR2C(O)R2b, NR2C(O)NR2R2a, CH(xe2x95x90NH)NH2, NHC(xe2x95x90NH)NH2, SO2NR2R2a, NR2SO2NR2R2a, and NR2SO2C1-4 alkyl;
R7, at each occurrence, is selected from H, OH, C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxy, C1-4 alkoxycarbonyl, (CH2)n-phenyl, C6-10 aryloxy, C6-10 aryloxycarbonyl, C6-10 arylmethylcarbonyl, C1-4 alkylcarbonyloxy C1-4 alkoxycarbonyl, C6-10 arylcarbonyloxy C1-4 alkoxycarbonyl, C1-6 alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C1-4 alkoxycarbonyl;
R8, at each occurrence, is selected from H, C1-6 alkyl and (CH2)n-phenyl;
alternatively, R7 and R8 combine to form a 5 or 6 membered saturated, ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
R9, at each occurrence, is selected from H, C1-6 alkyl and (CH2)n-phenyl;
n is selected from 0, 1, 2, and 3;
m is selected from 0, 1, and 2;
p is selected from 0, 1, and 2;
r is selected from 0, 1, 2, and 3;
s is selected from 0, 1, and 2; and,
t is selected from 0 and 1.
[2] In a preferred embodiment, the present invention provides a novel compound of formula Ia or Ib: 
wherein in formula Ia, rings Dxe2x80x94E represent a bicycle selected from the group: 1-aminoisoquinolin-7-yl; 1,3-diaminoisoquinolin-7-yl; 1,4-diaminoisoquinolin-7-yl; 1,5-diaminoisoquinolin-7-yl; 1,6-diaminoisoquinolin-7-yl; 1-amino-3-hydroxy-isoquinolin-7-yl; 1-amino-4-hydroxy-isoquinolin-7-yl; 1-amino-5-hydroxy-isoquinolin-7-yl; 1-amino-6-hydroxy-isoquinolin-7-yl; 1-amino-3-methoxy-isoquinolin-7-yl; 1-amino-4-methoxy-isoquinolin-7-yl; 1-amino-5-methoxy-isoquinolin-7-yl; 1-amino-6-methoxy-isoquinolin-7-yl; 1-hydroxy-isoquinolin-7-yl; 4-aminoquinazol-6-yl; 2,4-diaminoquinazol-6-yl; 4,7-diaminoquinazol-6-yl 4,8-diaminoquinazol-6-yl; 1-aminophthalaz-7-yl; 1,4-diaminophthalaz-7-yl; 1,5-diaminophthalaz-7-yl; 1,6-diaminophthalaz-7-yl; 4-aminopterid-6-yl; 2,4-aminopterid-6-yl; 4,6-diaminopterid-6-yl; 8-amino-1,7-naphthyrid-2-yl; 6,8-diamino-1,7-naphthyrid-2-yl; 5,8-diamino-1,7-naphthyrid-2-yl; 4,8-diamino-1,7-naphthyrid-2-yl; 3,8-diamino-1,7-naphthyrid-2-yl; 5-amino-2,6-naphthyrid-3-yl; 5,7-diamino-2,6-naphthyrid-3-yl; 5,8-diamino-2,6-naphthyrid-3-yl; 1,5-diamino-2,6-naphthyrid-3-yl; 5-amino-1,6-naphthyrid-3-yl; 5,7-diamino-1,6-naphthyrid-3-y; 5,8-diamino-1,6-naphthyrid-3-yl; 2,5-diamino-1,6-naphthyrid-3-yl; 3-aminoindazol-5-yl; 3-hydroxyindazol-5-yl; 3-aminobenzisoxazol-5-yl; 3-hydroxybenzisoxazol-5-yl; 3-aminobenzisothiazol-5-yl; 3-hydroxybenzisothiazol-5-yl; 1-amino-3,4-dihydroisoquinolin-7-yl; and, 1-aminoisoindol-6-yl;
alternatively, in formula Ia ring D is absent and ring G is phenyl or pyridyl and ring G is substituted with G and Rxe2x80x2:
G is selected from F, Cl, Br, I, OH, C1-3 alkoxy, CN, C(xe2x95x90NR8)NR7R9, NHC(xe2x95x90NR8)NR7R9, NR8CH(xe2x95x90NR7), C(O)NR7R8, (CR8R9)tNR7R8, SH, C1-3 alkyl-S, S(O)R3b, S(O)2R3a, S(O)2NR2R2a, and OCF3;
Rxe2x80x2 is selected from H, Cl, F, Br, I, (CH2)tOR3, C1-4 alkyl, OCF3, CF3, C(O)NR7R8, and (CR8R9)tNR7R8;
alternatively, in formula Ib, rings Dxe2x80x94E are selected from the group: 4-amino-pyrido[4,3-b]furan-3-yl, 4-amino-pyrido[4,3-b]furan-2-yl, 7-amino-pyrido[3,4-b]furan-2-yl, 4-amino-pyrido[4,3-b]thien-3-yl, 4-amino-pyrido[4,3-b]thien-2-yl, 7-amino-pyrido[3,4-b]thien-2-yl, 4-amino-5-aza-indol-3-yl, 4-amino-5-aza-indol-2-yl, 7-amino-6-aza-indol-3-yl, 4-amino-5-aza-indol-1-yl, 7-amino-pyrido[4,3-d]imidazol-1-yl, 4-amino-pyrido[3,4-d]imidazol-1-yl, 4-amino-5-aza-inden-3-yl, 4-amino-5-aza-inden-2-yl, 4-amino-5-aza-inden-1-yl, 4-amino-5-aza-dihydroinden-3-yl, 4-amino-5-aza-dihydroinden-2-yl, and 4-amino-5-aza-dihydroinden-1-yl;
M is selected from the group: 
Z is selected from (CH2)rC(O)(CH2)r, (CH2)rC(O)O(CH2)r, (CH2)rC(O)NR3(CH2)r, (CH2)rS(O)p(CH2)r, and (CH2)rSO2NR3(CH2)r;
R3d, at each occurrence, is selected from H and CH3;
A is selected from:
C5-6 carbocyclic residue substituted with 0-2 R4, and
5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
Xxe2x80x94Y combine to form a group selected from:
C(R3dR3e)C(R3dR3e), C(R3dR3e)C(R3dR3e)C(R3dR3e), NR4cC(R3dR3e), NR4cC(xe2x95x90O), NR4cC(R3dR3e)C(R3dR3e), NR4cC(R3dR3e)NR4c, NR4cC(xe2x95x90O)NR4c, NR4cC(xe2x95x90O)C(R3dR3e), C(R3dR3e)NR4c, C(R3dR3e)NR4cC(R3dR3e), and C(R3dR3e)C(R3dR3e)NR4c; and,
R4c, at each occurrence, is selected from H, C1-4 alkyl, CH2xe2x80x94CN, (CH2)2xe2x80x94CN, CH2xe2x80x94NR2R2a, (CH2)2NR2R2a, CH2C(O)R2c, and (CH2)2C(O)R2c.
[3] In a more preferred embodiment, the present invention provides a novel compound of formula Ia, wherein;
rings Dxe2x80x94E represent a bicycle selected from the group: 1-aminoisoquinolin-7-yl, 1,3-diaminoisoquinolin-7-yl, 1,4-diaminoisoquinolin-7-yl, 1,5-diaminoisoquinolin-7-yl, 1,6-diaminoisoquinolin-7-yl, 1-hydroxy-isoquinolin-7-yl, 4-aminoquinazol-6-yl, 2,4-diaminoquinazol-6-yl, 4,7-diaminoquinazol-6-yl, 4,8-diaminoquinazol-6-yl, 1-aminophthalaz-7-yl, 1,4-diaminophthalaz-7-yl, 1,5-diaminophthalaz-7-yl, 1,6-diaminophthalaz-7-yl, 4-aminopterid-6-yl, 8-amino-1,7-naphthyrid-2-yl, 5-amino-1,6-naphthyrid-3-y, 5-amino-2,6-naphthyrid-3-yl, 3-aminobenzisoxazol-5-yl, 3-aminobenzisothiazol-5-yl, 1-amino-3,4-dihydroisoquinolin-7-yl, and 1-aminoisoindol-6-yl;
alternatively, ring D is absent and ring G is phenyl or pyridyl and ring G is substituted with G and Rxe2x80x2:
G is selected from F, Cl, Br, and C1-3 alkoxy;
Rxe2x80x2 is selected from H, F, Cl, Br, OR3, and CH2OR3;
M is selected from the group: 
Z is selected from (CH2)rC(O)(CH2)r and (CH2)rC(O)NR3(CH2)r;
A is selected from:
C5-6 carbocyclic residue substituted with 0-2 R4, and
5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
Xxe2x80x94Y combine to form a group selected from: CH2CH2, NR4cCH2, NR4cC(xe2x95x90O), and CH2NR4c; and,
R4c, at each occurrence, is selected from H, CH2xe2x80x94CN, (CH2)2xe2x80x94CN, CH2xe2x80x94NR2R2a, and (CH2)2NR2R2a.
[4] In an even more preferred embodiment, the present invention provides a novel compound of formula Ia, wherein;
rings Dxe2x80x94E represent a bicycle selected from the group: 1-aminoisoquinolin-7-yl, 1,5-diaminoisoquinolin-7-yl, 1,6-diaminoisoquinolin-7-yl, 1-aminophthalaz-7-yl, 1,4-diaminophthalaz-7-yl, 1,5-diaminophthalaz-7-yl, 1,6-diaminophthalaz-7-yl, 4-aminopterid-6-yl, 8-amino-1,7-naphthyrid-2-yl, 5-amino-1,6-naphthyrid-3-y, 5-amino-2,6-naphthyrid-3-yl, 3-aminobenzisoxazol-5-yl, 4-amino-5-azabenzothiophen-2-yl, and, 1-aminoisoindol-6-yl;
alternatively, ring D is absent and ring E is phenyl substituted with G and Rxe2x80x2;
G is selected from CH2NH2, CH2NHCH3, CH(CH3)NH2, C(CH2)2NH2, F, Cl, Br, and OCH3;
Rxe2x80x2 is selected from H, OCH3, Cl, and F.
M is selected from the group: 
J is N;
R1a and R1b are independently absent or are xe2x80x94(CH2)rxe2x80x94R1xe2x80x2;
R1xe2x80x2 is selected from H, C1-3 alkyl, F, Cl, xe2x80x94CN, CF3, (CH2)rOR2, NR2R2a, C(O)R2c, OC(O)R2, S(O)pR2b, NR2C(O)R2b, C(O)NR2R2a, SO2NR2R2a, C3-6 carbocyclic residue substituted with 0-2 R4a, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;
A is selected from phenyl, pyridyl, pyrimidyl, pyridazinyl, and pyrazinyl and is substituted with 0-2 R4;
Xxe2x80x94Y combine to form NR4cCH2;
R2, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C5-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2a, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, phenethyl, C5-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2b, at each occurrence, is selected from CF3, C1-4 alkoxy, C1-6 alkyl, benzyl, C5-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2c, at each occurrence, is selected from CF3, OH, C1-4 alkoxy, C1-6 alkyl, benzyl, C5-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a ring selected from imidazolyl, morpholino, piperazinyl, pyridyl, and pyrrolidinyl, substituted with 0-2 R4b;
R4, at each occurrence, is selected from H, xe2x95x90O, OR2, CH2OR2, F, Cl, C1-4 alkyl, NR2R2a, CH2NR2R2a, C(O)R2c, CH2C(O)R2c, C(O)NR2R2a, SO2NR2R2a, NR2SO2xe2x80x94C1-4 alkyl, S(O)2R5, and CF3 
R4a, at each occurrence, is selected from H, (CH2)rOR2, F, Cl, C1-4 alkyl, NR2R2a, CH2NR2R2a, NR2R2b, CH2NR2R2b, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, NR2C(O)NR2R2a, SO2NR2R2a, S(O)2R5, and CF3;
R4b, at each occurrence, is selected from H, xe2x95x90O, (CH2)rOR3, F, Cl, C1-4 alkyl, NR3R3a, CH2NR3R3a, C(O)R3, CH2C(O)R3, C(O)OR3c, C(O)NR3R3a, SO2NR3R3a, NR3SO2xe2x80x94C1-4 alkyl, NR3SO2-phenyl, S(O)2xe2x80x94C1-4 alkyl, S(O)2-phenyl, and CF3; and,
R4c, at each occurrence, is selected from H, CH2xe2x80x94CN, (CH2)2xe2x80x94CN, CH2xe2x80x94NH2, and (CH2)2NH2.
[5] In a further preferred embodiment, the present invention provides a novel compound of formula Ia wherein:
rings Dxe2x80x94E represent a bicycle selected from the group: 1-aminoisoquinolin-7-yl, 1,5-diaminoisoquinolin-7-yl, 1,6-diaminoisoquinolin-7-yl, 8-amino-1,7-naphthyrid-2-yl, 5-amino-1,6-naphthyrid-3-y, 5-amino-2,6-naphthyrid-3-yl, 3-aminobenzisoxazol-5-yl, 1-aminophthalaz-7-yl, 4-amino-5-azabenzothiophen-2-yl, and, 1-aminoisoindol-6-yl; and,
alternatively, ring D is absent and Rxe2x80x2, G, and ring E form a group selected from 3-aminomethylphenyl, 4-fluoro-3-aminomethylphenyl, 4-fluoro-3-(methylaminomethyl)phenyl, 4-chloro-3-aminophenyl, and 2-aminomethylphenyl.
[6] In an even further preferred embodiment, the present invention provides a novel compound selected from:
N-[4-(1,1-dioxido-1,2-benzisothiazol-2-cyanomethyl-7-yl)phenyl]-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;
N-[4-(2,3-dihydro-1,1-dioxido-1,2-benzisothiazol-7-yl)phenyl]-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;
N-[4-(2,3-dihydro-3-hydroxy-1,1-dioxido-1,2-benzisothiazol-7-yl)phenyl]-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;
N-[4-[2-[2-(diethylamino)ethyl]-2,3-dihydro-1,1-dioxido-1,2-benzisothiazol-7-yl]phenyl]-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;
1-[3-(aminomethyl)phenyl]-N-[4-(2,3-dihydro-1,1-dioxido-1,2-benzisothiazol-7-yl)phenyl]-3-(trifluoromethyl)-1-H-pyrazole-5-carboxamide;
1-[3-(aminomethyl)phenyl]-N-[4-(2,3-dihydro-2-methyl-1,1-dioxido-1,2-benzisothiazol-7-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;
1-[3-(aminomethyl)-4-fluorophenyl]-N-[4-(2,3-dihydro-1,1-dioxido-1,2-benzisothiazol-7-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;
1-(3-amino-1,2-benzisoxazol-5-yl)-N-[4-(2,3-dihydro-1,1-dioxido-1,2-benzisothiazol-7-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;
1-[3-(aminoiminomethyl)phenyl]-N-[4-(2,3-dihydro-1,1-dioxido-1,2-benzisothiazol-7-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;
1-[3-(aminoiminomethyl)phenyl]-N-[4-(2,3-dihydro-2-methyl-1,1-dioxido-1,2-benzisothiazol-7-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;
1-[3-(aminoiminomethyl)phenyl]-N-[4-[2-[2-(diethylamino)ethyl]-2,3-dihydro-1,1-dioxido-1,2-benzisothiazol-7-yl]phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;
1-[3-(aminoiminomethyl)phenyl]-N-[4-(2,3-dihydro-1,1-dioxido-benzo[b]thiophen-7-yl))phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;
1-[3-(aminomethyl)phenyl]-N-[4-(2,3-dihydro-1,1-dioxido-benzo[b]thiophen-7-yl))phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;
1-(3-(amino-1,2-benzisoxazol-5-yl)-N-[4-(2,3-dihydro-2-methyl-1,1-dioxido-1,2-benzisothiazol-7-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;
1-(3-(amino-1,2-benzisoxazol-5-yl)-N-[4-[2-[2-(diethylamino)ethyl]-2,3-dihydro-1,1-dioxido-1,2-benzisothiazol-7-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;
1-(3-(amino-1,2-benzisoxazol-5-yl)-N-[4-(2,3-dihydro-1,1-dioxido-benzo[b]thiophen-7-yl))phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;
1-[3-(aminomethyl)phenyl]-N-[4-[2-[2-(diethylamino)ethyl]-2,3-dihydro-1,1-dioxido-1,2-benzisothiazol-7-yl]phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide
1-(3-amino-4-chlorophenyl)-N-[4-(2,3-dihydro-1,1-dioxido-1,2-benzisothiazol-7-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;
1-(3-amino-4-chlorophenyl)-N-[4-(2,3-dihydro-2-methyl-1,1-dioxido-1,2-benzisothiazol-7-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;
1-(3-amino-4-chlorophenyl)-N-[4-[2-[2-(diethylamino)ethyl]-2,3-dihydro-1,1-dioxido-1,2-benzisothiazol-7-yl]phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;
1-(3-amino-4-chlorophenyl)-N-[4-(2,3-dihydro-1,1-dioxido-benzo[b]thiophen-7-yl))phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;
1-[3-(aminoiminomethyl)phenyl]-N-[4-(2,3-dihydro-1,1-dioxido-1,2-benzisothiazol-7-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;
1-(1-amino-7-isoquinolinyl)-N-[4-(2,3-dihydro-1,1-dioxido-1,2-benzisothiazol-7-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;
1-(1-amino-7-isoquinolinyl)-N-[4-(2,3-dihydro-2-methyl-1,1-dioxido-1,2-benzisothiazol-7-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;
1-(1-amino-7-isoquinolinyl)-N-[4-[2-[2-(diethylamino)ethyl]-2,3-dihydro-1,1-dioxido-1,2-benzisothiazol-7-yl]phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;
1-(1-amino-7-isoquinolinyl)-N-[4-(2,3-dihydro-1,1-dioxido-benzo[b]thiophen-7-yl))phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;
1-(3-(amino-1,2-benzisoxazol-5-yl)-N-[4-(2,3-dihydro-1,1-dioxido-1,2-benzisothiazol-7-yl)phenyl]-1H-tetrazole-5-carboxamide;
1-(3-(amino-1,2-benzisoxazol-5-yl)-N-[4-(2,3-dihydro-1,1-dioxido-1,2-benzisothiazol-7-yl)phenyl]-3-(trifluoromethyl)-1H-1,2,4-triazole-5-carboxamide;
1-(3-(amino-1,2-benzisoxazol-5-yl)-N-[4-(2,3-dihydro-1,1-dioxido-1,2-benzisothiazol-7-yl)phenyl]-1H-1,2,3-triazole-5-carboxamide;
1-(3-(amino-1,2-benzisoxazol-5-yl)-N-[4-(2,3-dihydro-1,1-dioxido-1,2-benzisothiazol-7-yl)phenyl]-2-(trifluoromethyl)-5-thiazolecarboxamide; and,
1-(3-(amino-1,2-benzisoxazol-5-yl)-N-[4-(2,3-dihydro-1,1-dioxido-1,2-benzisothiazol-7-yl)phenyl]-4,5-dihydro-5-methyl-5-isoxazolecarboxamide;
or a pharmaceutically acceptable salt form thereof.
[7] In a prefered embodiment, rings Dxe2x80x94E combine to form a bicyclic moiety selected from the group: 
In another embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides novel compounds of formula (I) for use in therapy.
In another embodiment, the present invention provides the use of novel compounds of formula (I) for the manufacture of a medicament for the treatment of a thromboembolic disorder.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom-""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
When any variable (e.g., R6) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d or xe2x80x9calkylenexe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C1-10 alkyl (or alkylene), is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. xe2x80x9cAlkoxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C1-10 alkoxy, is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C3-7 cycloalkyl, is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. xe2x80x9cAlkenylxe2x80x9d or xe2x80x9calkenylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. C2-10 alkenyl (or alkenylene), is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkenyl groups. xe2x80x9cAlkynylxe2x80x9d or xe2x80x9calkynylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl. C2-10 alkynyl (or alkynylene), is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkynyl groups. xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic systemxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic systemxe2x80x9d or xe2x80x9cheteroarylxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and 1, 2, 3, or 4 heterotams independently selected from the group consisting of N, NH, O and S. It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc . . . ) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
xe2x80x9cSubstitutedxe2x80x9d is intended to indicate that one or more hydrogens on the atom indicated in the expression using xe2x80x9csubstitutedxe2x80x9d is replaced with a selection from the indicated group(s), provided that the indicated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O) group, then 2 hydrogens on the atom are replaced.
xe2x80x9cTherapeutically effective amountxe2x80x9d is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to treat the desired disease. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22: 27-55 (1984), occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased therapeutic effect, or some other beneficial effect of the combination compared with the individual components.
The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991). All references cited herein are hereby incorporated in their entirety herein by reference. 
Scheme 1 presents how the Axe2x80x94B unit could be assembled, followed by the linker formation. Boronic acid is prepared according to the procedure by Pinto (WO 98/28269) and coupled with 5-bromo cyclic sulfone derivative (1) under Suzuki conditions. Deprotection of the aniline could be accomplished either with sodium borohydride in methanol or under standard basic conditions (lithium hydroxide in aqueous tetrahydrofuran). Coupling to the core ring structures (I) could be accomplished according to the standard procedures known to the practitioners of the art. 
Scheme 2 illustrates the preparation of 5-bromosultam derivatives. Conversion of the dibromoaniline to the dibromobenzenesulfonyl chloride can be accomplished according to the modified procedure by G. Wittig (Organic Synthesis, Coll. Vol.5, 60), followed by the coupling with the appropriately substituted amine in the basic media. To achieve a metal-halogen exchange, the intermediate is treated with n-BuLi as shown by J. Wrobel (Heterocycles, Vol.38, 1823, 1994). The generated lithium anion could be quenched by the addition of N, N-dimethyl formamide. Deprotection and xcex2-elimination can be achieved simultaneously under acidic conditions and is followed by the reduction of the imine bond with the appropriate reducing agent. Protection of the nitrogen of the final sultam derivative could be achieved with the number of the desired groups following the standard synthetic procedures commonly known in the art. Saccharine-like derivatives (3) could be obtained upon the treatment with an appropriate oxidizing agent, followed by the deprotection and introduction of the desired R3 group. 
Scheme 3 describes the synthesis of the desired azasultam derivative (4) by warming of the intermediate dibromophenylsulfonyl hydrazide in a basic media. Synthesis of the 6-ring aza-sultam (5) could proceed under halogen-metal exchange conditions described in Scheme 2 followed by the xcex2-elimination and reduction to afford the desired compound. 
In Scheme 4 dibromophenylsulfonyl chloride can be reduced to the corresponding sulfinic acid upon the treatment with sodium borohydride as described by A. Nose (Chem. Pharm. Bull. 35, 1770, 1987). The sulfinic acid undergoes Mannich condensation with formaldehyde and t-butyl amine as in A. Kanazawa (J. Org. Chem., 59, 1232, 1994) to afford an intermediate that undergoes halogen-metal exchange as was shown in Scheme 2 to give the 6-ring cyclic sulfone. Deprotection and xcex2-elimination can be achieved simultaneously under acidic conditions and is followed by the reduction of the imine bond with the appropriate reducing agent as described in Scheme 2. Protection of the nitrogen of the final derivative (7) could be achieved with the number of the desired groups following the standard synthetic procedures commonly known in the art. Additionally, the intermediate aminomethyl sulfone can be cyclized to the desired 5-ring aza-sulfone (6) upon heating in the basic media. 
In Scheme 5 the sulfinic acid (Scheme 4) is treated with formaldehyde and disubstituted hydrazine to afford an intermediate that upon heating in the basic medium can cyclize to the final compound (8). 
Scheme 6 describes the synthesis of the desired 6-ring saccharin derivative (9), where the dibromophenylsulfonylamide (Scheme 2) undergoes the palladium mediated coupling with TMS acetylene (Singh, J. Org. Chem. 54, 4453, 1989) to provide the intermediate that is converted to the acid upon deprotection and treatment with the base as described by V. Laishev (Zh. Org. Khim.17, 2064, 1981). Final amide bond formation could be accomplished using the standard conditions known in the art. 
In Scheme 7 the treatment of the starting material under halogen-metal exchange conditions described in Scheme 2, followed by the quenching of the reaction medium with dibromoethane can affords the final 6-ring sultam derivative (10). 
In Scheme 8 the reduction to the dibromophenylmethyl sulfone can be done according to the procedure by L. Field (Organic Synthesis, Coll. Vol. 4, 674). Halogen-metal exchange of this sulfone upon the treatment with n-BuLi according to the modified procedure by A. Cabidu, (Synthesis, 1, 41, 1993) followed by the quench with N,N-dimethyl formamide affords the cyclic 5-ring sulfone (11) after xcex2-elimination and reduction of the intermediate imine. The treatment of the phenyl methylsulfone under similar halogen-metal exchange conditions and quenching with dibromoethane can provide the desired 6-ring cyclic sulfone (12). 
Scheme 9 describes the synthesis of 6-ring heterocyclic sulfone derivatives (13 and 14). Synthesis of the dibromo sulfonamide is described in scheme 2. Amination is accomplished according to the procedure by A. Wisansky (Organic Synthesis, IV, 307, 1955). Treatment with phosgene can lead to the desired sulfonylcyclic urea derivative (13). Additionally, treatment of the intermediate aminobromophenyl sulfonamide with N, N-dimethylformamide in the basic media, followed by the reduction of the imine leads to the 6-ring azasultam (14).